Fgfr2 inhibitors for the treatment of cholangiocarcinoma

ABSTRACT

Disclosed herein are methods of treating cholangiocarcinoma in a patient comprising: evaluating a biological sample from the patient for the presence of one or more FGFR mutants including at least the FGFR2 SNP C383R; and treating the patient with an FGFR inhibitor if one or more FGFR mutants including at least the FGFR2 SNP C383R are present in the sample.

TECHNICAL FIELD

Provided herein are methods of treating cholangiocarcinoma in a patientharboring one or more FGFR mutants with a fibroblast growth factorreceptor inhibitor.

BACKGROUND

The identification of genetic abnormalities can be useful in selectingthe appropriate therapeutic(s) for cancer patients. This is also usefulfor cancer patients failing the main therapeutic option (front-linetherapy) for that cancer type, particularly if there is no acceptedstandard of care for second and subsequent-line therapy. Fibroblastgrowth factor receptors (FGFRs) are a family of receptor tyrosinekinases involved in regulating cell survival, proliferation, migrationand differentiation. FGFR alterations including FGFR mutations and FGFRfusions or translocations have been observed in some cancers. To date,there are no approved therapies that are efficacious in patients withFGFR alterations.

SUMMARY

Disclosed herein are methods of treating cholangiocarcinoma in a patientcomprising: evaluating a biological sample from the patient for thepresence of one or more FGFR mutants; and treating the patient with anFGFR inhibitor if one or more FGFR mutants are present in the sample.

Disclosed herein are methods of treating cholangiocarcinoma in a patientcomprising: evaluating a biological sample from the patient for thepresence of one or more FGFR mutants including at least the FGFR2 SNPC383R; or one or more FGFR mutants including at least the fusionFGFR2-BICC1; or one or more FGFR mutants including at least the fusionFGFR2-CCAR1; or one or more FGFR mutants including at least the fusionFGFR2-KIAA1598; or one or more FGFR mutants including at least thefusion DTWD2-FGFR2; or one or more FGFR mutants including at least thefusion ESR2-FGFR2; or one or more FGFR mutants including at least thefusion FGFR2-MGEA5; or one or more FGFR mutants including at least thefusion FGFR2-SBNO2; or one or more FGFR mutants including at least themutation FGFR2 C390>YS; or one or more FGFR mutants including at leastthe mutation FGFR2 N549K; in particular for the presence of one or moreFGFR mutants including at least the FGFR2 C383R; and treating thepatient with an FGFR inhibitor if one or more FGFR mutants as describedabove are present in the sample; in particular treating the patient withan FGFR inhibitor if one or more FGFR mutants including at least theFGFR2 SNP C383R are present in the sample.

Disclosed herein are methods of treating cholangiocarcinoma in a patientharboring the FGFR2 SNP C383R, or harboring the fusion FGFR2-BICC1; orharboring the fusion FGFR2-CCAR1; or harboring the fusionFGFR2-KIAA1598; or harboring the fusion DTWD2-FGFR2; or harboring thefusion ESR2-FGFR2; or harboring the fusion FGFR2-MGEA5; or harboring thefusion FGFR2-SBNO2; or harboring the mutation FGFR2 C390>YS; orharboring the mutation FGFR2 N549K; in particular harboring FGFR2 C383R,comprising administering a FGFR inhibitor to said patient. The patientmay comprise one or more further FGFR mutants.

Disclosed herein is a FGFR inhibitor for use in the treatment ofcholangiocarcinoma in a patient harboring the FGFR2 SNP C383R, orharboring the fusion FGFR2-BICC1; or harboring the fusion FGFR2-CCAR1;or harboring the fusion FGFR2-KIAA1598; or harboring the fusionDTWD2-FGFR2; or harboring the fusion ESR2-FGFR2; or harboring the fusionFGFR2-MGEA5; or harboring the fusion FGFR2-SBNO2; or harboring themutation FGFR2 C390>YS; or harboring the mutation FGFR2 N549K; inparticular harboring FGFR2 C383R. The patient may comprise one or morefurther FGFR mutants.

Disclosed herein is the use of a FGFR inhibitor in the manufacture of amedicament for the treatment of cholangiocarcinoma in a patientharboring the FGFR2 SNP C383R, or harboring the fusion FGFR2-BICC1; orharboring the fusion FGFR2-CCAR1; or harboring the fusionFGFR2-KIAA1598; or harboring the fusion DTWD2-FGFR2; or harboring thefusion ESR2-FGFR2; or harboring the fusion FGFR2-MGEA5; or harboring thefusion FGFR2-SBNO2; or harboring the mutation FGFR2 C390>YS; orharboring the mutation FGFR2 N549K; in particular harboring FGFR2 C383R.The patient may comprise one or more further FGFR mutants.

Disclosed herein is a FGFR inhibitor for use in the treatment ofcholangiocarcinoma in a patient wherein the patient is identified asbeing responsive or likely to respond to the treatment with the FGFRinhibitor by evaluating a biological sample obtained from the patientfor the presence of one or more FGFR mutants including at least theFGFR2 SNP C383R; or one or more FGFR mutants including at least thefusion FGFR2-BICC1; or one or more FGFR mutants including at least thefusion FGFR2-CCAR1; or one or more FGFR mutants including at least thefusion FGFR2-KIAA1598; or one or more FGFR mutants including at leastthe fusion DTWD2-FGFR2; or one or more FGFR mutants including at leastthe fusion ESR2-FGFR2; or one or more FGFR mutants including at leastthe fusion FGFR2-MGEA5; or one or more FGFR mutants including at leastthe fusion FGFR2-SBNO2; or one or more FGFR mutants including at leastthe mutation FGFR2 C390>YS; or one or more FGFR mutants including atleast the mutation FGFR2 N549K; in particular for the presence of one ormore FGFR mutants including at least the FGFR2 C383R, wherein thepresence of one or more FGFR mutants including at least the FGFR2 SNPC383R; or one or more FGFR mutants including at least the fusionFGFR2-BICC1; or one or more FGFR mutants including at least the fusionFGFR2-CCAR1; or one or more FGFR mutants including at least the fusionFGFR2-KIAA1598; or one or more FGFR mutants including at least thefusion DTWD2-FGFR2; or one or more FGFR mutants including at least thefusion ESR2-FGFR2; or one or more FGFR mutants including at least thefusion FGFR2-MGEA5; or one or more FGFR mutants including at least thefusion FGFR2-SBNO2; or one or more FGFR mutants including at least themutation FGFR2 C390>YS; or one or more FGFR mutants including at leastthe mutation FGFR2 N549K; in particular wherein the presence of one ormore FGFR mutants including at least the FGFR2 C383R is detected.

Disclosed herein is the use of a FGFR inhibitor for the manufacture of amedicament for the treatment of cholangiocarcinoma in a patient whereinthe patient is identified as being responsive or likely to respond tothe treatment with the FGFR inhibitor by evaluating a biological sampleobtained from the patient for the presence of one or more FGFR mutantsincluding at least the FGFR2 SNP C383R; or one or more FGFR mutantsincluding at least the fusion FGFR2-BICC1; or one or more FGFR mutantsincluding at least the fusion FGFR2-CCAR1; or one or more FGFR mutantsincluding at least the fusion FGFR2-KIAA1598; or one or more FGFRmutants including at least the fusion DTWD2-FGFR2; or one or more FGFRmutants including at least the fusion ESR2-FGFR2; or one or more FGFRmutants including at least the fusion FGFR2-MGEA5; or one or more FGFRmutants including at least the fusion FGFR2-SBNO2; or one or more FGFRmutants including at least the mutation FGFR2 C390>YS; or one or moreFGFR mutants including at least the mutation FGFR2 N549K; in particularfor the presence of one or more FGFR mutants including at least theFGFR2 C383R, wherein the presence of one or more FGFR mutants includingat least the FGFR2 SNP C383R; or one or more FGFR mutants including atleast the fusion FGFR2-BICC1; or one or more FGFR mutants including atleast the fusion FGFR2-CCAR1; or one or more FGFR mutants including atleast the fusion FGFR2-KIAA1598; or one or more FGFR mutants includingat least the fusion DTWD2-FGFR2; or one or more FGFR mutants includingat least the fusion ESR2-FGFR2; or one or more FGFR mutants including atleast the fusion FGFR2-MGEA5; or one or more FGFR mutants including atleast the fusion FGFR2-SBNO2; or one or more FGFR mutants including atleast the mutation FGFR2 C390>YS; or one or more FGFR mutants includingat least the mutation FGFR2 N549K; in particular wherein the presence ofone or more FGFR mutants including at least the FGFR2 C383R is detected.

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

Reference to a particular numerical value includes at least thatparticular value, unless the context clearly dictates otherwise. When arange of values is expressed, another embodiment includes from the oneparticular value and/or to the other particular value. Further,reference to values stated in ranges include each and every value withinthat range. All ranges are inclusive and combinable.

The following abbreviations are used throughout the specification: FGFR(fibroblast growth factor receptor); FFPET (Formalin-FixedParaffin-Embedded Tissue); SNP (single nucleotide polymorphism).

As used herein, “treating” and like terms refer to reducing the severityand/or frequency of cancer symptoms, eliminating cancer symptoms and/orthe underlying cause of said symptoms, reducing the frequency orlikelihood of cancer symptoms and/or their underlying cause, andimproving or remediating damage caused, directly or indirectly, bycancer.

“Biological samples” refers to any sample from a patient in whichcancerous cells can be obtained and detection of a FGFR mutant ispossible. Suitable biological samples include, but are not limited to,blood, lymph fluid, bone marrow, a solid tumor sample, or anycombination thereof. In some embodiments, the biological sample can beFFPET.

FGFR Mutants

As used herein, the phrase “FGFR mutant” refers to a FGFR fusion gene, aFGFR single nucleotide polymorphism, a FGFR mutation or all of these. Inan embodiment, the phrase “FGFR mutant” refers to a FGFR fusion gene, aFGFR single nucleotide polymorphism, or both. In an embodiment, thephrase “FGFR mutant” refers to a FGFR fusion gene. In an embodiment, thephrase “FGFR mutant” refers to a FGFR mutation.

“FGFR fusion” or “FGFR fusion gene” refers to a gene encoding FGFR(e.g., FGRF2 or FGFR3), or a portion thereof, and a fusion partner, orportion thereof, created by a translocation between the two genes. Thepresence of one or more FGFR fusion genes in a biological sample from apatient can be determined using the disclosed methods or usingappropriate methods described in literature.

“FGFR single nucleotide polymorphism” (SNP) refers to a FGFR2 or FGFR3gene in which a single nucleotide differs among individuals. A specificFGFR SNP in the methods of treatment or uses disclosed herein is FGFR2C383R. The presence of one or more FGFR SNPs in a biological sample froma patient can be determined using the disclosed methods or usingappropriate methods described in literature.

Whenever used herein FGFR2 SNP C383R or FGFR2 C383R denotes a FGFR2mutation in which cysteine in position 383 is replaced by arginine. Theterms may be used interchangeable.

FGFR Inhibitors for Use in the Disclosed Methods or Uses

Suitable FGFR inhibitors for use in the disclosed methods are providedherein.

In some embodiments, if one or more FGFR mutants including at least theFGFR2 SNP C383R are present in the sample, the cholangiocarcinomapatient can be treated with a FGFR inhibitor disclosed in U.S. Publ. No.2013/0072457 A1 (incorporated herein by reference), including anytautomeric or stereochemically isomeric form thereof, and a N-oxidethereof, a pharmaceutically acceptable salt thereof, or a solvatethereof (suitable R groups are also disclosed in U.S. Publ. No.2013/0072457 A1). In some aspects, for example, the patient can betreated withN-(3,5-dimethoxy-phenyl)-N′-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine(referred to herein as “JNJ-42756493” or “JNJ493” or erdafitinib):

including a N-oxide thereof, a pharmaceutically acceptable salt thereof,or a solvate thereof. In some aspects, the pharmaceutically acceptablesalt is a HCl salt. In some aspects, the patient can be treated withJNJ493 base.

In some embodiments, the cholangiocarcinoma patient can be treated witha FGFR inhibitor if one or more FGFR mutants including at least theFGFR2 SNP C383R are present in the sample, wherein the FGFR inhibitor isN-[5-[2-(3,5-Di-methoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-(3,5-diemthylpiperazin-1-yl)benzamide(AZD4547), as described in Gavine, P. R., et al., AZD4547: An OrallyBioavailable, Potent, and Selective Inhibitor of the Fibroblast GrowthFactor Receptor Tyrosine Kinase Family, Cancer Res. Apr. 15, 2012 72;2045:

including, when chemically possible, any tautomeric or stereochemicallyisomeric form thereof, and a N-oxide thereof, a pharmaceuticallyacceptable salt thereof, or a solvate thereof.

In some embodiments, the cholangiocarcinoma patient can be treated witha FGFR inhibitor if one or more FGFR mutants including at least theFGFR2 SNP C383R are present in the sample, wherein the FGFR inhibitor is3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimid-4-yl}-1-methyl-urea(NVP-BGJ398) as described in Int'l Publ. No. WO2006/000420:

including, when chemically possible, any tautomeric or stereochemicallyisomeric form thereof, and a N-oxide thereof, a pharmaceuticallyacceptable salt thereof, or a solvate thereof.

In some embodiments, the cholangiocarcinoma patient can be treated witha FGFR inhibitor if one or more FGFR mutants including at least theFGFR2 SNP C383R are present in the sample, wherein the FGFR inhibitor is4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-quinolin-2-one(dovitinib) as described in Int't Publ. No. WO2006/127926:

including, when chemically possible, any tautomeric or stereochemicallyisomeric form thereof, and a N-oxide thereof, a pharmaceuticallyacceptable salt thereof, or a solvate thereof.

In some embodiments, the cholangiocarcinoma patient can be treated witha FGFR inhibitor if one or more FGFR mutants including at least theFGFR2 SNP C383R are present in the sample, wherein the FGFR inhibitor is6-(7-((1-Amino-cyclopropyl)-methoxy)-6-methoxyquinolin-4-yloxy)-N-methyl-1-naphthamide(AL3810) (lucitanib; E-3810), as described in Bello, E. et al., E-3810Is a Potent Dual Inhibitor of VEGFR and FGFR that Exerts AntitumorActivity in Multiple Preclinical Models, Cancer Res Feb. 15, 201171(A)1396-1405 and Int'l Publ. No. WO2008/112408:

including, when chemically possible, any tautomeric or stereochemicallyisomeric form thereof, and a N-oxide thereof, a pharmaceuticallyacceptable salt thereof, or a solvate thereof.

In some embodiments, the cholangiocarcinoma patient can be treated witha FGFR inhibitor if one or more FGFR mutants including at least theFGFR2 SNP C383R are present in the sample, wherein the FGFR inhibitor isan anti-FGFR2 antibody such as that described in WO2013/076186.

Additional suitable FGFR inhibitors include BAY1163877 (Bayer),BAY1179470 (Bayer), TAS-120 (Taiho), ARQ087 (ArQule), ASP5878(Astellas), FF284 (Chugai), FP-1039 (GSK/FivePrime), Blueprint,LY-2874455 (Lilly), RG-7444 (Roche), or any combination thereof,including, when chemically possible, any tautomeric or stereochemicallyisomeric forms thereof, N-oxides thereof, pharmaceutically acceptablesalts thereof, or solvates thereof.

In some embodiments, the cholangiocarcinoma patient can be treated witha FGFR inhibitor if one or more FGFR mutants including at least theFGFR2 SNP C383R are present in the sample, wherein the FGFR inhibitor isBAY1163877 (Bayer), including, when chemically possible, any tautomericor stereochemically isomeric form thereof, N-oxide thereof,pharmaceutically acceptable salt thereof, or solvate thereof.

In some embodiments, the cholangiocarcinoma patient can be treated witha FGFR inhibitor if one or more FGFR mutants including at least theFGFR2 SNP C383R are present in the sample, wherein the FGFR inhibitor isBAY1179470 (Bayer), including, when chemically possible, any tautomericor stereochemically isomeric form thereof, N-oxide thereof,pharmaceutically acceptable salt thereof, or solvate thereof.

In some embodiments, the cholangiocarcinoma patient can be treated witha FGFR inhibitor if one or more FGFR mutants including at least theFGFR2 SNP C383R are present in the sample, wherein the FGFR inhibitor isTAS-120 (Taiho), including, when chemically possible, any tautomeric orstereochemically isomeric form thereof, N-oxide thereof,pharmaceutically acceptable salt thereof, or solvate thereof.

In some embodiments, the cholangiocarcinoma patient can be treated witha FGFR inhibitor if one or more FGFR mutants including at least theFGFR2 SNP C383R are present in the sample, wherein the FGFR inhibitor isARQ087 (ArQule), including, when chemically possible, any tautomeric orstereochemically isomeric form thereof, N-oxide thereof,pharmaceutically acceptable salt thereof, or solvate thereof.

In some embodiments, the cholangiocarcinoma patient can be treated witha FGFR inhibitor if one or more FGFR mutants including at least theFGFR2 SNP C383R are present in the sample, wherein the FGFR inhibitor isASP5878 (Astellas), including, when chemically possible, any tautomericor stereochemically isomeric form thereof, N-oxide thereof,pharmaceutically acceptable salt thereof, or solvate thereof.

In some embodiments, the cholangiocarcinoma patient can be treated witha FGFR inhibitor if one or more FGFR mutants including at least theFGFR2 SNP C383R are present in the sample, wherein the FGFR inhibitor isFF284 (Chugai), including, when chemically possible, any tautomeric orstereochemically isomeric form thereof, N-oxide thereof,pharmaceutically acceptable salt thereof, or solvate thereof.

In some embodiments, the cholangiocarcinoma patient can be treated witha FGFR inhibitor if one or more FGFR mutants including at least theFGFR2 SNP C383R are present in the sample, wherein the FGFR inhibitor isFP-1039 (GSK/FivePrime), including, when chemically possible, anytautomeric or stereochemically isomeric form thereof, N-oxide thereof,pharmaceutically acceptable salt thereof, or solvate thereof.

In some embodiments, the cholangiocarcinoma patient can be treated witha FGFR inhibitor if one or more FGFR mutants including at least theFGFR2 SNP C383R are present in the sample, wherein the FGFR inhibitor isBlueprint, including, when chemically possible, any tautomeric orstereochemically isomeric form thereof, N-oxide thereof,pharmaceutically acceptable salt thereof, or solvate thereof.

In some embodiments, the cholangiocarcinoma patient can be treated witha FGFR inhibitor if one or more FGFR mutants including at least theFGFR2 SNP C383R are present in the sample, wherein the FGFR inhibitor isLY-2874455 (Lilly), including, when chemically possible, any tautomericor stereochemically isomeric form thereof, N-oxide thereof,pharmaceutically acceptable salt thereof, or solvate thereof.

In some embodiments, the cholangiocarcinoma patient can be treated witha FGFR inhibitor if one or more FGFR mutants including at least theFGFR2 SNP C383R are present in the sample, wherein the FGFR inhibitor isRG-7444 (Roche), including, when chemically possible, any tautomeric orstereochemically isomeric form thereof, N-oxide thereof,pharmaceutically acceptable salt thereof, or solvate thereof.

Salts can be synthesized from a parent compound that contains a basic oracidic moiety by conventional chemical methods such as methods describedin Pharmaceutical Salts: Properties, Selection, and Use, P. HeinrichStahl (Editor), Camille G. Wermuth (Editor), ISBN: 3-90639-026-8,Hardcover, 388 pages, August 2002, which is incorporated herein byreference. Generally, such salts can be prepared by reacting the freeacid or base forms of these compounds with the appropriate base or acidin water or in an organic solvent, or in a mixture of the two;generally, nonaqueous media such as ether, ethyl acetate, ethanol,isopropanol, or acetonitrile are used. The FGFR inhibitors for use inthe disclosed methods may exist as mono- or di-salts depending upon thepKa of the acid from which the salt is formed.

Acid addition salts may be formed with a wide variety of acids, bothinorganic and organic. Examples of acid addition salts include saltsformed with an acid including, but not limited to, acetic,2,2-dichloroacetic, adipic, alginic, ascorbic (e.g. L-ascorbic),L-aspartic, benzenesulphonic, benzoic, 4-acetamidobenzoic, butanoic, (+)camphoric, camphor-sulphonic, (+)-(1S)-camphor-10-sulphonic, capric,caproic, caprylic, cinnamic, citric, cyclamic, dodecylsulphuric,ethane-1,2-disulphonic, ethanesulphonic, 2-hydroxyethanesulphonic,formic, fumaric, galactaric, gentisic, glucoheptonic, D-gluconic,glucuronic (e.g. D-glucuronic), glutamic (e.g. L-glutamic),α-oxoglutaric, glycolic, hippuric, hydrobromic, hydrochloric, hydriodic,isethionic, lactic (e.g. (+)-L-lactic, (+)-DL-lactic), lactobionic,maleic, malic, (−)-L-malic, malonic, (+)-DL-mandelic, methanesulphonic,naphthalenesulphonic (e.g. naphthalene-2-sulphonic),naphthalene-1,5-disulphonic, 1-hydroxy-2-naphthoic, nicotinic, nitric,oleic, orotic, oxalic, palmitic, pamoic, phosphoric, propionic,L-pyroglutamic, pyruvic, salicylic, 4-amino-salicylic, sebacic, stearic,succinic, sulphuric, tannic, (+)-L-tartaric, thiocyanic,toluenesulphonic (e.g. p-toluenesulphonic), undecylenic and valericacids, as well as acylated amino acids and cation exchange resins.

One particular group of salts consists of salts formed from acetic,hydrochloric, hydriodic, phosphoric, nitric, sulphuric, citric, lactic,succinic, maleic, malic, isethionic, fumaric, benzenesulphonic,toluenesulphonic, methanesulphonic (mesylate), ethanesulphonic,naphthalenesulphonic, valeric, propanoic, butanoic, malonic, glucuronicand lactobionic acids. Another group of acid addition salts includessalts formed from acetic, adipic, ascorbic, aspartic, citric, DL-Lactic,fumaric, gluconic, glucuronic, hippuric, hydrochloric, glutamic,DL-malic, methanesulphonic, sebacic, stearic, succinic and tartaricacids.

If the compound is anionic, or has a functional group which may beanionic (e.g., —COOH may be —COO⁻), then a salt may be formed with asuitable cation. Examples of suitable inorganic cations include, but arenot limited to, alkali metal ions such as Na⁺ and K⁺, alkaline earthmetal cations such as Ca²⁺ and Mg²⁺, and other cations such as Al³⁺.Examples of suitable organic cations include, but are not limited to,ammonium ion (i.e., NH₄ ⁺) and substituted ammonium ions (e.g., NH₃R⁺,NH₂R₂ ⁺, NHR₃ ⁺, NR₄+).

Examples of some suitable substituted ammonium ions are those derivedfrom: ethylamine, diethylamine, dicyclohexylamine, triethylamine,butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine,benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, aswell as amino acids, such as lysine and arginine. An example of a commonquaternary ammonium ion is N(CH₃)₄ ⁺.

Where the compounds contain an amine function, these may form quaternaryammonium salts, for example by reaction with an alkylating agentaccording to methods well known to the skilled person. Such quaternaryammonium compounds are within the scope of the disclosed compounds.Compounds containing an amine function may also form N-oxides. Areference herein to a compound that contains an amine function alsoincludes the N-oxide. Where a compound contains several amine functions,one or more than one nitrogen atom may be oxidised to form an N-oxide.Particular examples of N-oxides are the N-oxides of a tertiary amine ora nitrogen atom of a nitrogen-containing heterocycle. N-Oxides can beformed by treatment of the corresponding amine with an oxidizing agentsuch as hydrogen peroxide or a per-acid (e.g. a peroxycarboxylic acid),see for example Advanced Organic Chemistry, by Jerry March, 4^(th)Edition, Wiley Interscience, pages. More particularly, N-oxides can bemade by the procedure of L. W. Deady (Syn. Comm. (1977), 7, 509-514) inwhich the amine compound is reacted with m-chloroperoxybenzoic acid(MCPBA), for example, in an inert solvent such as dichloromethane.

As used herein, the term “solvate” means a physical association of thecompound with one or more solvent molecules. This physical associationinvolves varying degrees of ionic and covalent bonding, includinghydrogen bonding. In certain instances the solvate will be capable ofisolation, for example when one or more solvent molecules areincorporated in the crystal lattice of the crystalline solid. The term“solvate” is intended to encompass both solution-phase and isolatablesolvates. Non-limiting examples of suitable solvates include thedisclosed compounds in combination with water, isopropanol, ethanol,methanol, DMSO, ethyl acetate, acetic acid, ethanolamine and the like.The compound may exert its biological effects while in solution.

Solvates are well known in pharmaceutical chemistry. They can beimportant to the processes for the preparation of a substance (e.g. inrelation to their purification), the storage of the substance (e.g. itsstability) and the ease of handling of the substance, and are oftenformed as part of the isolation or purification stages of a chemicalsynthesis. A person skilled in the art can determine by means ofstandard and long used techniques whether a hydrate or other solvate hasformed by the isolation conditions or purification conditions used toprepare a given compound. Examples of such techniques includethermogravimetric analysis (TGA), differential scanning calorimetry(DSC), X-ray crystallography (e.g. single crystal X-ray crystallographyor X-ray powder diffraction) and Solid State NMR (SS-NMR, also known asMagic Angle Spinning NMR or MAS-NMR). Such techniques are as much a partof the standard analytical toolkit of the skilled chemist as NMR, IR,HPLC and MS. Alternatively the skilled person can deliberately form asolvate using crystallisation conditions that include an amount of thesolvent required for the particular solvate. Thereafter the standardmethods described above, can be used to establish whether solvates hadformed. Also encompassed are any complexes (e.g. inclusion complexes orclathrates with compounds such as cyclodextrins, or complexes withmetals) of the FGFR inhibitor.

Furthermore, the compound may have one or more polymorph (crystalline)or amorphous forms.

The compounds include compounds with one or more isotopic substitutions,and a reference to a particular element includes within its scope allisotopes of the element. For example, a reference to hydrogen includeswithin its scope ¹H, ²H (D), and ³H (T). Similarly, references to carbonand oxygen include within their scope respectively ¹²C, ¹³C and ¹⁴C and¹⁶O and ¹⁸O. The isotopes may be radioactive or non-radioactive. In oneembodiment, the compounds contain no radioactive isotopes. Suchcompounds are preferred for therapeutic use. In another embodiment,however, the compound may contain one or more radioisotopes. Compoundscontaining such radioisotopes may be useful in a diagnostic context.

In some embodiments, the cholangiocarcinoma patient is treated with aFGFR inhibitor if one or more FGFR mutants including at least the FGFR2SNP C383R are present in the sample, wherein the FGFR inhibitor isN-(3,5-dimethoxyphenyl)-N′-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine(referred to herein “JNJ-42756493”), or a pharmaceutically acceptablesalt thereof or a solvate thereof. In an embodiment the FGFR inhibitoris JNJ-42756493 base.

Methods of Treating Cancer in a Patient

Disclosed herein are methods of treating cholangiocarcinoma in a patientcomprising: evaluating a biological sample from the patient for thepresence of one or more FGFR mutants including at least the FGFR2 SNPC383R; and treating the patient with an FGFR inhibitor if one or moreFGFR mutants including at least the FGFR2 SNP C383R are present in thesample. In an embodiment, the FGFR inhibitor is erdafitinib.

Disclosed herein are methods of treating cholangiocarcinoma in a patientharboring the FGFR2 SNP C383R comprising administering a FGFR inhibitorto said patient. The patient may comprise one or more further FGFRmutants. In an embodiment, the FGFR inhibitor is erdafitinib.

Disclosed herein is a FGFR inhibitor for use in the treatment ofcholangiocarcinoma in a patient harboring the FGFR2 SNP C383R. Thepatient may comprise one or more further FGFR mutants. In an embodiment,the FGFR inhibitor is erdafitinib.

Disclosed herein is the use of a FGFR inhibitor in the manufacture of amedicament for the treatment of cholangiocarcinoma in a patientharboring the FGFR2 SNP C383R. The patient may comprise one or morefurther FGFR mutants. In an embodiment, the FGFR inhibitor iserdafitinib.

Disclosed herein is a FGFR inhibitor for use in the treatment ofcholangiocarcinoma in a patient wherein the patient is identified asbeing responsive or likely to respond to the treatment with the FGFRinhibitor by evaluating a biological sample obtained from the patientfor the presence of one or more FGFR mutants including at least theFGFR2 SNP C383R, wherein the presence of one or more FGFR mutantsincluding at least the FGFR2 SNP C383R is detected. In an embodiment,the FGFR inhibitor is erdafitinib.

Disclosed herein is the use of a FGFR inhibitor for the manufacture of amedicament for the treatment of cholangiocarcinoma in a patient whereinthe patient is identified as being responsive or likely to respond tothe treatment with the FGFR inhibitor by evaluating a biological sampleobtained from the patient for the presence of one or more FGFR mutantsincluding at least the FGFR2 SNP C383R, wherein the presence of one ormore FGFR mutants including at least the FGFR2 SNP C383R is detected. Inan embodiment, the FGFR inhibitor is erdafitinib.

In an embodiment, erdafitinib is administered at a dose of 10 mg.

In an embodiment, erdafitinib is administered at a dose of 10 mgintermittently.

In an embodiment, erdafitinib is administered at a dose of 10 mgintermittently 7 days on/7 days off.

In an embodiment, erdafitinib is administered at a dose of 8 mg, inparticular 8 mg once daily. In an embodiment, erdafitinib isadministered at a dose of 8 mg, in particular 8 mg once daily, with anoption to uptitrate to 9 mg depending on serum phosphate levels (e.g.serum phosphate levels are <5.5 mg/dL, or are <7 mg/dL or range from andinclude 7 mg/dL to ≤9 mg/dL or are ≤9 mg/dL), and depending ontreatment-related adverse events observed. In an embodiment, the levelsof serum phosphate for determining whether or not to up-titrate aremeasured on a treatment day during the first cycle of erdafitinibtreatment, in particular on day 14±2 days, more in particular on day 14,of erdafitinib administration.

In an embodiment of the invention, in the methods of treatment and theuses as described herein the FGFR2 SNP C383R may be replaced by the FGFRfusion FGFR2-BICC1.

Disclosed herein are methods of treating cholangiocarcinoma in a patientcomprising: evaluating a biological sample from the patient for thepresence of one or more FGFR mutants including at least FGFR2-BICC1; andtreating the patient with an FGFR inhibitor if one or more FGFR mutantsincluding at least FGFR2-BICC1 are present in the sample. In anembodiment, the FGFR inhibitor is erdafitinib.

Disclosed herein are methods of treating cholangiocarcinoma in a patientharboring FGFR2-BICC1 comprising administering a FGFR inhibitor to saidpatient. The patient may comprise one or more further FGFR mutants. Inan embodiment, the FGFR inhibitor is erdafitinib.

Disclosed herein is a FGFR inhibitor for use in the treatment ofcholangiocarcinoma in a patient harboring FGFR2-BICC1. The patient maycomprise one or more further FGFR mutants. In an embodiment, the FGFRinhibitor is erdafitinib.

Disclosed herein is the use of a FGFR inhibitor in the manufacture of amedicament for the treatment of cholangiocarcinoma in a patientharboring FGFR2-BICC1. The patient may comprise one or more further FGFRmutants. In an embodiment, the FGFR inhibitor is erdafitinib.

Disclosed herein is a FGFR inhibitor for use in the treatment ofcholangiocarcinoma in a patient wherein the patient is identified asbeing responsive or likely to respond to the treatment with the FGFRinhibitor by evaluating a biological sample obtained from the patientfor the presence of one or more FGFR mutants including at leastFGFR2-BICC1, wherein the presence of one or more FGFR mutants includingat least FGFR2-BICC1 is detected. In an embodiment, the FGFR inhibitoris erdafitinib.

Disclosed herein is the use of a FGFR inhibitor for the manufacture of amedicament for the treatment of cholangiocarcinoma in a patient whereinthe patient is identified as being responsive or likely to respond tothe treatment with the FGFR inhibitor by evaluating a biological sampleobtained from the patient for the presence of one or more FGFR mutantsincluding at least FGFR2-BICC1, wherein the presence of one or more FGFRmutants including at least FGFR2-BICC1 is detected. In an embodiment,the FGFR inhibitor is erdafitinib.

In an embodiment of the invention, in the methods of treatment and theuses as described herein the FGFR2 SNP C383R may be replaced by the FGFRfusion FGFR2-CCAR1.

Disclosed herein are methods of treating cholangiocarcinoma in a patientcomprising: evaluating a biological sample from the patient for thepresence of one or more FGFR mutants including at least FGFR2-CCAR1; andtreating the patient with an FGFR inhibitor if one or more FGFR mutantsincluding at least FGFR2-CCAR1 are present in the sample. In anembodiment, the FGFR inhibitor is erdafitinib.

Disclosed herein are methods of treating cholangiocarcinoma in a patientharboring FGFR2-CCAR1 comprising administering a FGFR inhibitor to saidpatient. The patient may comprise one or more further FGFR mutants. Inan embodiment, the FGFR inhibitor is erdafitinib.

Disclosed herein is a FGFR inhibitor for use in the treatment ofcholangiocarcinoma in a patient harboring FGFR2-CCAR1. The patient maycomprise one or more further FGFR mutants. In an embodiment, the FGFRinhibitor is erdafitinib.

Disclosed herein is the use of a FGFR inhibitor in the manufacture of amedicament for the treatment of cholangiocarcinoma in a patientharboring FGFR2-CCAR1. The patient may comprise one or more further FGFRmutants. In an embodiment, the FGFR inhibitor is erdafitinib.

Disclosed herein is a FGFR inhibitor for use in the treatment ofcholangiocarcinoma in a patient wherein the patient is identified asbeing responsive or likely to respond to the treatment with the FGFRinhibitor by evaluating a biological sample obtained from the patientfor the presence of one or more FGFR mutants including at leastFGFR2-CCAR1, wherein the presence of one or more FGFR mutants includingat least FGFR2-CCAR1 is detected. In an embodiment, the FGFR inhibitoris erdafitinib.

Disclosed herein is the use of a FGFR inhibitor for the manufacture of amedicament for the treatment of cholangiocarcinoma in a patient whereinthe patient is identified as being responsive or likely to respond tothe treatment with the FGFR inhibitor by evaluating a biological sampleobtained from the patient for the presence of one or more FGFR mutantsincluding at least FGFR2-CCAR1, wherein the presence of one or more FGFRmutants including at least FGFR2-CCAR1 is detected. In an embodiment,the FGFR inhibitor is erdafitinib.

In an embodiment of the invention, in the methods of treatment and theuses as described herein the FGFR2 SNP C383R may be replaced by the FGFRfusion FGFR2-KIAA1598.

Disclosed herein are methods of treating cholangiocarcinoma in a patientcomprising: evaluating a biological sample from the patient for thepresence of one or more FGFR mutants including at least FGFR2-KIAA1598;and treating the patient with an FGFR inhibitor if one or more FGFRmutants including at least FGFR2-KIAA1598 are present in the sample. Inan embodiment, the FGFR inhibitor is erdafitinib.

Disclosed herein are methods of treating cholangiocarcinoma in a patientharboring FGFR2-KIAA1598 comprising administering a FGFR inhibitor tosaid patient. The patient may comprise one or more further FGFR mutants.In an embodiment, the FGFR inhibitor is erdafitinib.

Disclosed herein is a FGFR inhibitor for use in the treatment ofcholangiocarcinoma in a patient harboring FGFR2-KIAA1598. The patientmay comprise one or more further FGFR mutants. In an embodiment, theFGFR inhibitor is erdafitinib.

Disclosed herein is the use of a FGFR inhibitor in the manufacture of amedicament for the treatment of cholangiocarcinoma in a patientharboring FGFR2-KIAA1598. The patient may comprise one or more furtherFGFR mutants. In an embodiment, the FGFR inhibitor is erdafitinib.

Disclosed herein is a FGFR inhibitor for use in the treatment ofcholangiocarcinoma in a patient wherein the patient is identified asbeing responsive or likely to respond to the treatment with the FGFRinhibitor by evaluating a biological sample obtained from the patientfor the presence of one or more FGFR mutants including at leastFGFR2-KIAA1598, wherein the presence of one or more FGFR mutantsincluding at least FGFR2-KIAA1598 is detected. In an embodiment, theFGFR inhibitor is erdafitinib.

Disclosed herein is the use of a FGFR inhibitor for the manufacture of amedicament for the treatment of cholangiocarcinoma in a patient whereinthe patient is identified as being responsive or likely to respond tothe treatment with the FGFR inhibitor by evaluating a biological sampleobtained from the patient for the presence of one or more FGFR mutantsincluding at least FGFR2-KIAA1598, wherein the presence of one or moreFGFR mutants including at least FGFR2-KIAA1598 is detected. In anembodiment, the FGFR inhibitor is erdafitinib.

In an embodiment of the invention, in the methods of treatment and theuses as described herein the FGFR2 SNP C383R may be replaced by the FGFRfusion DTWD2-FGFR2.

Disclosed herein are methods of treating cholangiocarcinoma in a patientcomprising: evaluating a biological sample from the patient for thepresence of one or more FGFR mutants including at least DTWD2-FGFR2; andtreating the patient with an FGFR inhibitor if one or more FGFR mutantsincluding at least DTWD2-FGFR2 are present in the sample. In anembodiment, the FGFR inhibitor is erdafitinib.

Disclosed herein are methods of treating cholangiocarcinoma in a patientharboring DTWD2-FGFR2 comprising administering a FGFR inhibitor to saidpatient. The patient may comprise one or more further FGFR mutants. Inan embodiment, the FGFR inhibitor is erdafitinib.

Disclosed herein is a FGFR inhibitor for use in the treatment ofcholangiocarcinoma in a patient harboring DTWD2-FGFR2. The patient maycomprise one or more further FGFR mutants. In an embodiment, the FGFRinhibitor is erdafitinib.

Disclosed herein is the use of a FGFR inhibitor in the manufacture of amedicament for the treatment of cholangiocarcinoma in a patientharboring FGFR2-DTWD2-FGFR2. The patient may comprise one or morefurther FGFR mutants. In an embodiment, the FGFR inhibitor iserdafitinib.

Disclosed herein is a FGFR inhibitor for use in the treatment ofcholangiocarcinoma in a patient wherein the patient is identified asbeing responsive or likely to respond to the treatment with the FGFRinhibitor by evaluating a biological sample obtained from the patientfor the presence of one or more FGFR mutants including at leastDTWD2-FGFR2, wherein the presence of one or more FGFR mutants includingat least DTWD2-FGFR2 is detected. In an embodiment, the FGFR inhibitoris erdafitinib.

Disclosed herein is the use of a FGFR inhibitor for the manufacture of amedicament for the treatment of cholangiocarcinoma in a patient whereinthe patient is identified as being responsive or likely to respond tothe treatment with the FGFR inhibitor by evaluating a biological sampleobtained from the patient for the presence of one or more FGFR mutantsincluding at least DTWD2-FGFR2, wherein the presence of one or more FGFRmutants including at least DTWD2-FGFR2 is detected. In an embodiment,the FGFR inhibitor is erdafitinib.

In an embodiment of the invention, in the methods of treatment and theuses as described herein the FGFR2 SNP C383R may be replaced by the FGFRfusion ESR2-FGFR2.

Disclosed herein are methods of treating cholangiocarcinoma in a patientcomprising: evaluating a biological sample from the patient for thepresence of one or more FGFR mutants including at least ESR2-FGFR2; andtreating the patient with an FGFR inhibitor if one or more FGFR mutantsincluding at least ESR2-FGFR2 are present in the sample. In anembodiment, the FGFR inhibitor is erdafitinib.

Disclosed herein are methods of treating cholangiocarcinoma in a patientharboring ESR2-FGFR2 comprising administering a FGFR inhibitor to saidpatient. The patient may comprise one or more further FGFR mutants. Inan embodiment, the FGFR inhibitor is erdafitinib.

Disclosed herein is a FGFR inhibitor for use in the treatment ofcholangiocarcinoma in a patient harboring ESR2-FGFR2. The patient maycomprise one or more further FGFR mutants. In an embodiment, the FGFRinhibitor is erdafitinib.

Disclosed herein is the use of a FGFR inhibitor in the manufacture of amedicament for the treatment of cholangiocarcinoma in a patientharboring ESR2-FGFR2. The patient may comprise one or more further FGFRmutants. In an embodiment, the FGFR inhibitor is erdafitinib.

Disclosed herein is a FGFR inhibitor for use in the treatment ofcholangiocarcinoma in a patient wherein the patient is identified asbeing responsive or likely to respond to the treatment with the FGFRinhibitor by evaluating a biological sample obtained from the patientfor the presence of one or more FGFR mutants including at leastESR2-FGFR2, wherein the presence of one or more FGFR mutants includingat least ESR2-FGFR2 is detected. In an embodiment, the FGFR inhibitor iserdafitinib.

Disclosed herein is the use of a FGFR inhibitor for the manufacture of amedicament for the treatment of cholangiocarcinoma in a patient whereinthe patient is identified as being responsive or likely to respond tothe treatment with the FGFR inhibitor by evaluating a biological sampleobtained from the patient for the presence of one or more FGFR mutantsincluding at least ESR2-FGFR2, wherein the presence of one or more FGFRmutants including at least ESR2-FGFR2 is detected. In an embodiment, theFGFR inhibitor is erdafitinib.

In an embodiment of the invention, in the methods of treatment and theuses as described herein the FGFR2 SNP C383R may be replaced by the FGFRfusion FGFR2-MGEA5.

Disclosed herein are methods of treating cholangiocarcinoma in a patientcomprising: evaluating a biological sample from the patient for thepresence of one or more FGFR mutants including at least FGFR2-MGEA5; andtreating the patient with an FGFR inhibitor if one or more FGFR mutantsincluding at least FGFR2-MGEA5 are present in the sample. In anembodiment, the FGFR inhibitor is erdafitinib.

Disclosed herein are methods of treating cholangiocarcinoma in a patientharboring FGFR2-MGEA5 comprising administering a FGFR inhibitor to saidpatient. The patient may comprise one or more further FGFR mutants. Inan embodiment, the FGFR inhibitor is erdafitinib.

Disclosed herein is a FGFR inhibitor for use in the treatment ofcholangiocarcinoma in a patient harboring FGFR2-MGEA5. The patient maycomprise one or more further FGFR mutants. In an embodiment, the FGFRinhibitor is erdafitinib.

Disclosed herein is the use of a FGFR inhibitor in the manufacture of amedicament for the treatment of cholangiocarcinoma in a patientharboring FGFR2-MGEA5. The patient may comprise one or more further FGFRmutants. In an embodiment, the FGFR inhibitor is erdafitinib.

Disclosed herein is a FGFR inhibitor for use in the treatment ofcholangiocarcinoma in a patient wherein the patient is identified asbeing responsive or likely to respond to the treatment with the FGFRinhibitor by evaluating a biological sample obtained from the patientfor the presence of one or more FGFR mutants including at leastFGFR2-MGEA5, wherein the presence of one or more FGFR mutants includingat least FGFR2-MGEA5 is detected. In an embodiment, the FGFR inhibitoris erdafitinib.

Disclosed herein is the use of a FGFR inhibitor for the manufacture of amedicament for the treatment of cholangiocarcinoma in a patient whereinthe patient is identified as being responsive or likely to respond tothe treatment with the FGFR inhibitor by evaluating a biological sampleobtained from the patient for the presence of one or more FGFR mutantsincluding at least FGFR2-MGEA5, wherein the presence of one or more FGFRmutants including at least FGFR2-MGEA5 is detected. In an embodiment,the FGFR inhibitor is erdafitinib.

In an embodiment of the invention, in the methods of treatment and theuses as described herein the FGFR2 SNP C383R may be replaced by the FGFRfusion FGFR2-SBNO2.

Disclosed herein are methods of treating cholangiocarcinoma in a patientcomprising: evaluating a biological sample from the patient for thepresence of one or more FGFR mutants including at least FGFR2-SBNO2; andtreating the patient with an FGFR inhibitor if one or more FGFR mutantsincluding at least FGFR2-SBNO2 are present in the sample. In anembodiment, the FGFR inhibitor is erdafitinib.

Disclosed herein are methods of treating cholangiocarcinoma in a patientharboring FGFR2-SBNO2 comprising administering a FGFR inhibitor to saidpatient. The patient may comprise one or more further FGFR mutants. Inan embodiment, the FGFR inhibitor is erdafitinib.

Disclosed herein is a FGFR inhibitor for use in the treatment ofcholangiocarcinoma in a patient harboring FGFR2-SBNO2. The patient maycomprise one or more further FGFR mutants. In an embodiment, the FGFRinhibitor is erdafitinib.

Disclosed herein is the use of a FGFR inhibitor in the manufacture of amedicament for the treatment of cholangiocarcinoma in a patientharboring FGFR2-SBNO2. The patient may comprise one or more further FGFRmutants. In an embodiment, the FGFR inhibitor is erdafitinib.

Disclosed herein is a FGFR inhibitor for use in the treatment ofcholangiocarcinoma in a patient wherein the patient is identified asbeing responsive or likely to respond to the treatment with the FGFRinhibitor by evaluating a biological sample obtained from the patientfor the presence of one or more FGFR mutants including at leastFGFR2-SBNO2, wherein the presence of one or more FGFR mutants includingat least FGFR2-SBNO2 is detected. In an embodiment, the FGFR inhibitoris erdafitinib.

Disclosed herein is the use of a FGFR inhibitor for the manufacture of amedicament for the treatment of cholangiocarcinoma in a patient whereinthe patient is identified as being responsive or likely to respond tothe treatment with the FGFR inhibitor by evaluating a biological sampleobtained from the patient for the presence of one or more FGFR mutantsincluding at least FGFR2-SBNO2, wherein the presence of one or more FGFRmutants including at least FGFR2-SBNO2 is detected. In an embodiment,the FGFR inhibitor is erdafitinib.

In an embodiment of the invention, in the methods of treatment and theuses as described herein the FGFR2 SNP C383R may be replaced by the FGFRmutation FGFR2 C390>YS.

Disclosed herein are methods of treating cholangiocarcinoma in a patientcomprising: evaluating a biological sample from the patient for thepresence of one or more FGFR mutants including at least FGFR2 C390>YS;and treating the patient with an FGFR inhibitor if one or more FGFRmutants including at least FGFR2 C390>YS are present in the sample. Inan embodiment, the FGFR inhibitor is erdafitinib.

Disclosed herein are methods of treating cholangiocarcinoma in a patientharboring FGFR2 C390>YS comprising administering a FGFR inhibitor tosaid patient. The patient may comprise one or more further FGFR mutants.In an embodiment, the FGFR inhibitor is erdafitinib.

Disclosed herein is a FGFR inhibitor for use in the treatment ofcholangiocarcinoma in a patient harboring FGFR2 C390>YS. The patient maycomprise one or more further FGFR mutants. In an embodiment, the FGFRinhibitor is erdafitinib.

Disclosed herein is the use of a FGFR inhibitor in the manufacture of amedicament for the treatment of cholangiocarcinoma in a patientharboring FGFR2 C390>YS. The patient may comprise one or more furtherFGFR mutants. In an embodiment, the FGFR inhibitor is erdafitinib.

Disclosed herein is a FGFR inhibitor for use in the treatment ofcholangiocarcinoma in a patient wherein the patient is identified asbeing responsive or likely to respond to the treatment with the FGFRinhibitor by evaluating a biological sample obtained from the patientfor the presence of one or more FGFR mutants including at least FGFR2C390>YS, wherein the presence of one or more FGFR mutants including atleast FGFR2 C390>YS is detected. In an embodiment, the FGFR inhibitor iserdafitinib.

Disclosed herein is the use of a FGFR inhibitor for the manufacture of amedicament for the treatment of cholangiocarcinoma in a patient whereinthe patient is identified as being responsive or likely to respond tothe treatment with the FGFR inhibitor by evaluating a biological sampleobtained from the patient for the presence of one or more FGFR mutantsincluding at least FGFR2 C390>YS, wherein the presence of one or moreFGFR mutants including at least FGFR2 C390>YS is detected. In anembodiment, the FGFR inhibitor is erdafitinib.

In an embodiment of the invention, in the methods of treatment and theuses as described herein the FGFR2 SNP C383R may be replaced by the FGFRmutation FGFR2 N549K.

Disclosed herein are methods of treating cholangiocarcinoma in a patientcomprising: evaluating a biological sample from the patient for thepresence of one or more FGFR mutants including at least FGFR2 N549K; andtreating the patient with an FGFR inhibitor if one or more FGFR mutantsincluding at least FGFR2 N549K are present in the sample. In anembodiment, the FGFR inhibitor is erdafitinib.

Disclosed herein are methods of treating cholangiocarcinoma in a patientharboring FGFR2 N549K comprising administering a FGFR inhibitor to saidpatient. The patient may comprise one or more further FGFR mutants. Inan embodiment, the FGFR inhibitor is erdafitinib.

Disclosed herein is a FGFR inhibitor for use in the treatment ofcholangiocarcinoma in a patient harboring FGFR2 N549K. The patient maycomprise one or more further FGFR mutants. In an embodiment, the FGFRinhibitor is erdafitinib.

Disclosed herein is the use of a FGFR inhibitor in the manufacture of amedicament for the treatment of cholangiocarcinoma in a patientharboring FGFR2 N549K. The patient may comprise one or more further FGFRmutants. In an embodiment, the FGFR inhibitor is erdafitinib.

Disclosed herein is a FGFR inhibitor for use in the treatment ofcholangiocarcinoma in a patient wherein the patient is identified asbeing responsive or likely to respond to the treatment with the FGFRinhibitor by evaluating a biological sample obtained from the patientfor the presence of one or more FGFR mutants including at least FGFR2N549K, wherein the presence of one or more FGFR mutants including atleast FGFR2 N549K is detected. In an embodiment, the FGFR inhibitor iserdafitinib.

Disclosed herein is the use of a FGFR inhibitor for the manufacture of amedicament for the treatment of cholangiocarcinoma in a patient whereinthe patient is identified as being responsive or likely to respond tothe treatment with the FGFR inhibitor by evaluating a biological sampleobtained from the patient for the presence of one or more FGFR mutantsincluding at least FGFR2 N549K, wherein the presence of one or more FGFRmutants including at least FGFR2 N549K is detected. In an embodiment,the FGFR inhibitor is erdafitinib.

In an embodiment, the proportion of cholangiocarcinoma patients, inparticular advanced cholangiocarcinoma patients, with at least one ofthe FGFR mutants as described herein showing objective response rate isat least 15%, or 20%, or 25%, or 30%, or 35%, or 40%, or 45%, or above45%.

Methods of identification and analysis of FGFR mutants such as forexample the FGFR2 SNP C383R can be performed using techniques known to aperson skilled in the art and as described herein such asreverse-transcriptase polymerase chain reaction (RT-PCR) or in-situhybridization such as fluorescence in situ hybridization (FISH). Thediagnostic tests and screens are typically conducted on a biologicalsample selected from tumour biopsy samples, blood samples (isolation andenrichment of shed tumour cells), or as described hereinabove. Thescreening process will typically involve direct sequencing,oligonucleotide microarray analysis, or a mutant specific antibody.

In screening by RT-PCR, the level of mRNA in the tumour is assessed bycreating a cDNA copy of the mRNA followed by amplification of the cDNAby PCR. Methods of PCR amplification, the selection of primers, andconditions for amplification, are known to a person skilled in the art.Nucleic acid manipulations and PCR are carried out by standard methods,as described for example in Ausubel, F. M. et al., eds. (2004) CurrentProtocols in Molecular Biology, John Wiley & Sons Inc., or Innis, M. A.et al., eds. (1990) PCR Protocols: a guide to methods and applications,Academic Press, San Diego. Reactions and manipulations involving nucleicacid techniques are also described in Sambrook et al., (2001), 3^(rd)Ed, Molecular Cloning: A Laboratory Manual, Cold Spring HarborLaboratory Press. Alternatively a commercially available kit for RT-PCR(for example Roche Molecular Biochemicals) may be used, or methodologyas set forth in U.S. Pat. Nos. 4,666,828; 4,683,202; 4,801,531;5,192,659, 5,272,057, 5,882,864, and 6,218,529 and incorporated hereinby reference. An example of an in-situ hybridisation technique forassessing mRNA expression would be fluorescence in-situ hybridisation(FISH) (see Angerer (1987) Meth. Enzymol., 152: 649).

Generally, in situ hybridization comprises the following major steps:(1) fixation of tissue to be analyzed; (2) prehybridization treatment ofthe sample to increase accessibility of target nucleic acid, and toreduce nonspecific binding; (3) hybridization of the mixture of nucleicacids to the nucleic acid in the biological structure or tissue; (4)post-hybridization washes to remove nucleic acid fragments not bound inthe hybridization, and (5) detection of the hybridized nucleic acidfragments. The probes used in such applications are typically labelled,for example, with radioisotopes or fluorescent reporters. Preferredprobes are sufficiently long, for example, from about 50, 100, or 200nucleotides to about 1000 or more nucleotides, to enable specifichybridization with the target nucleic acid(s) under stringentconditions. Standard methods for carrying out FISH are described inAusubel, F. M. et al., eds. (2004) Current Protocols in MolecularBiology, John Wiley & Sons Inc and Fluorescence In Situ Hybridization:Technical Overview by John M. S. Bartlett in Molecular Diagnosis ofCancer, Methods and Protocols, 2nd ed.; ISBN: 1-59259-760-2; March 2004,pps. 077-088; Series: Methods in Molecular Medicine.

Mutations and fusions are described herein with reference to thereference sequence NCBI Reference Sequence: NM_000141.4 and itscorresponding amino acid sequence.

FGFR2 C383R denotes an FGFR2 mutation in which cysteine in position 383is replaced by arginine.FGFR2 C390>YS describes an FGFR2 mutation in which cysteine in position390 is replaced by tyrosine and serine.FGFR2 N549K describes an FGFR2 mutation in which asparagine in position549 is replaced by lysine.FGFR2-KIAA1598 is a 5′-FGFR2 (ex1-17)-KIAA1598 (ex7-15)-3′ fusion withREARR-POS1 chr10:123242270-123242562 and REARR-POS2chr10:118709031-118709262 or with REARR-POS1 chr10:123242809-123243080and REARR-POS2 chr10:118710247-118710599.DTWD2-FGFR2 is a 5′-DTWD2(ex1)-FGFR2(ex18)-3′ fusion with REARR-POS1chr10:123242450-123242723 and REARR-POS2 chr5:118322151-118322550.ESR2-FGFR2 is a 5′-ESR2 (ex1-3)-FGFR2 (ex18)-3′ fusion with REARR-POS1chr10: 123239893-123240042 and REARR-POS2 chr14:64740210-64740315FGFR2-MGEA5 is a 5′-FGFR2(ex1-17)-MGEA5(ex11-16)-3′ fusion withREARR-POS1 chr10:123241032-123241358 and REARR-POS2chr10:103557129-103557439.FGFR2-BICC1 is a 5′-FGFR2(ex1-17)-BICC1(ex3-21)-3′ fusion withREARR-POS1 chr10: 123242218-123242771 and REARR-POS2chr10:60445416-60445560.FGFR2-SBNO2 is a 5′-FGFR2(x18)-SBNO2(x19-32)-3′fusion with REARR-POS1chr10:123240725-123240921 and REARR-POS2 chr19:1113573-1113710.

EXAMPLES

1) Treatment of Patients with Cholangiocarcinoma

A clinical trial was conducted in which patients age ≥18 years wereenrolled with advanced solid tumours for which standard curative therapywas no longer effective (NCT01703481; 4 part study).

-   -   Dose escalation (Part 1, all corners) followed a 3+3 design,        with patients receiving ascending doses of erdafitinib at 0.5,        2, 4, 6, 9, and 12 mg QD (21-day cycles).    -   After daily dose escalation (Part 1), two intermittent doses        were also evaluated at 10 and 12 mg 7 days on/7 days off (28-day        cycles).    -   Subsequent parts (Parts 2-4) required documented FGFR-biomarker        positive disease.    -   Part 2 (pharmacodynamics cohort, all corners) and Part 3        (dose-expansion cohort for recommended phase 2 dose of 9 mg QD,        cholangiocarcinoma in addition to other cancers):    -   Tumors were required to be KRAS wild type and have any of the        following: FGFR amplifications, FGFR activating mutations, FGFR        translocations, or other aberrations of FGFR activation.    -   Part 4 (dose-expansion cohort for 10 mg intermittently,        cholangiocarcinoma in addition to other cancers):    -   Tumors were required to have FGFR activating mutations or FGFR        translocations.    -   Serial blood samples were collected to measure erdafinitib        concentrations in plasma in Parts 1 and 2. Sparse samples were        collected in Parts 3 and 4.

Results

Eleven patients with FGFR-aberrant cholangiocarcinoma were treated at 9mg QD (n=1, Part 3) or 10 mg intermittent (n=10, Part 4).

-   Of the 11 patients: 3 (27.3%) harbored FGFR mutations, and 8 (72.7%)    harbored translocations.    Median treatment duration was 5.3 mo (range, 1 to 16 mo).    Patients received a median of 6 cycles (range, 2 to 17).    Most patients had received ≥6 cycles (8/11; 72.7%), including 4    (36.4%) treated with ≥9 cycles.    Systemic erdafitinib exposure in cholangiocarcinoma patients was    similar to patients in all other cancer indications in this study.    Of the 3 partial responses, 1 patient had a FGFR mutation (FGFR2    C383R) and 2 had FGFR translocations (fusions of FGFR2-BICC1 [n=1]    and FGFR2-CCAR1 [n=1]).    Overall disease control rate, including stable disease, was 54.5%    (6/11).    With a median follow-up of 5.5 mo:    -   Median duration of response was 11.4 mo (95% CI, 9.9 to 12.9        mo).    -   Median progression-free survival was 5.1 mo (95% CI 1.6 to 11.8        mo).    -   6- and 9-mo progression-free survival rates were 36% and 24%,        respectively.    -   As of the cutoff date, 1 patient continues on study treatment.

The objective response rate was 27.3% with a median duration of responseof 11.4 months for erdafitinib 9 mg QD or 10 mg intermittent in thisheavily pretreated population, with all responses seen at the latterdosing schedule.

The disease control rate was 54.5%.

Safety and PK data were consistent with those from the previouslypublished results from Part 1 of this study (Tabemero J, et al: J ClinOncol 33:3401-3408, 2015).

2) Treatment of Patients with Cholangiocarcinoma

A Study to evaluate the clinical efficacy of JNJ-42756493 (Erdafitinib),in Asian participants with advanced Non-Small-Cell Lung Cancer,Urothelial Cancer, Esophageal Cancer or Cholangiocarcinoma.(NCT02699606; LUC2001).

LUC2001 is an open-label, multicenter, phase 2a study including advancedcholangiocarcinoma subjects with FGFR alterations, based onFoundationOne testing, who failed at least 1 prior systemic treatment.The primary endpoint is objective response rate (ORR; by ResponseEvaluation Criteria in Solid Tumors (RECIST) version 1.1). The secondaryendpoints are disease control rate (DCR), safety and pharmacokinetics.Disease is evaluated every 8 weeks until disease progression (PD).Participants receive 8 mg erdafitinib starting dose once daily withoption to uptitrate to 9 mg on a 28-day cycle. The dose of the drug maybe modified, delayed, or terminated based on guidelines in the protocol.

Inclusion Criteria:

-   -   Pathologically or cytologically confirmed, advanced or        refractory tumors (there are no restriction on the total number        of lines of prior therapies, but participant should have        received at least 1 line of anti-cancer therapy [as per local        standard of care]): Squamous and non-squamous non-small-cell        lung cancer (NSCLC), esophageal cancer, urothelial cancer and        cholangiocarcinoma    -   Participants must meet the following molecular eligibility        criteria (diagnosed at a central or local laboratory using        either a tumor tissue based assay, which must indicate: at least        one of following): a) fibroblast growth factor receptor (FGFR)        gene translocations b) FGFR gene mutations that are considered        activating c) Participants with evidence of FGFR pathway        activation or other potential target/pathway inhibited by        erdafitinib may also be considered and allowed for enrollment if        supported by emerging biomarker data.    -   The presence of measurable disease according to the Response        Evaluation Criteria in Solid Tumors (RECIST, Version 1.1)        Criteria, and documented disease progression as defined by        RECIST (Version 1.1) at baseline    -   Eastern Cooperative Oncology Group (ECOG) performance status        score 0 or 1    -   Female participants (of child bearing potential and sexually        active) and male participants (with a partner of child bearing        potential) must use medically acceptable methods of birth        control. Male participants must use highly effective birth        control measurements when sexually active and must not donate        sperm    -   Adequate bone marrow, liver, and renal function within the 14        days prior to Day 1 of Cycle 1 up until pre-dose of Cycle 1

Exclusion Criteria:

-   -   Chemotherapy, targeted therapies, immunotherapy, or treatment        with an investigational anticancer agent within 2 weeks or at        least 5 half-lives of the drug whichever is longer up to a        maximum of 4 weeks before the first administration of study        drug. Localized palliative radiation therapy (but should not        include radiation to target lesions) and ongoing luteinizing        hormone-releasing hormone (LHRH) agonists, bisphosphonates and        denosumab, are permitted    -   Participants with persistent phosphate greater than (>) upper        limit of normal (ULN) during Screening (within 14 days prior to        Day 1 of Cycle 1 up until pre-dose of Cycle 1) and despite        medical management of phosphate levels

Participants taking medications known to have a significant risk ofcausing QTc prolongation and Torsades de Pointes. Participants who havediscontinued any of these medications must have a wash-out period of atleast 5 days or at least 5 half-lives of the drug (whichever is longer)prior to the first dose of study drug

Left ventricular ejection fraction (LVEF) less than (<) 50% as assessedby echocardiography (or multi-gated acquisition [MUGA]) performed atScreening

-   -   Uncontrolled inter-current illness including, but not limited        to, poorly controlled hypertension or diabetes, ongoing active        infection requiring antibiotics, psychiatric illness,        uncontrolled cardiovascular disease, or at risk of        gastrointestinal perforation as per investigators' assessment    -   Received prior selective FGFR inhibitor treatment or RET        inhibitor treatment, respectively according to the biomarker        prescreening result, or if the participant has known allergies,        hypersensitivity, or intolerance to Erdafitinib or its        excipients Any corneal or retinal abnormality likely to increase        risk of eye toxicity

All sexes Eligible for Study. Participants are 18 years and older.

Advanced cholangiocarcinoma patients who progressed after first-linechemotherapy have limited treatment options and poor prognosis.

Preliminary Results (Snapshot): As of 20 Mar. 2018, 150 advancedcholangiocarcinoma patients were molecularly screened and 25 had FGFRalterations, of whom 11 were dosed with 8 mg qd erdafitinib, allresponse evaluable. Median age was 53.0 years and ECOG score 0/1 in 6and 5 subjects respectively. Median number of treatment cycles was 4.0and median treatment duration was 3.5 months. There were 3 partialresponse (PR), 2 unconfirmed PR (uPR), 4 stable disease (SD), and 2 PD.The ORR (CR+PR+uCR+uPR) is 45.5%. The DCR (CR+PR+uCR+uPR+SD) is 81.8%.Six subjects are still on treatment. All subjects experienced AEs, 7experienced Grade 3 or worse AEs, 3 experienced serious AEs (SAEs) withno drug related SAE, all had AEs leading to drug interruption, 3 had AEsleading to dose reduction, while no AE led to treatment discontinuationor death. The most common AEs (>30%) were hyperphosphatemia (8/11), drymouth (7/11), stomatitis (7/11), diarrhea (4/11), nail disorder (4/11),and palmar-plantar erythrodysaesthesia syndrome (4/11).

The participants with confirmed or unconfirmed partial response includeparticipants with FGFR2-KIAA1598 and DTWD2-FGFR2 fusions, withESR2-FGFR2 fusion, with FGFR2 C390>YS mutation and with FGFR2-MGEA5fusion.

The participants with stable disease include participants withFGFR2-BICC1 fusion, with FGFR2 fusion with SBNO2 partner, with FGFR2N549K mutation, and with FGFR2-KIAA1598 fusion.

Conclusion: PK characteristics are consistent with data from othererdafitinib studies. Erdafitinib showed encouraging clinical activityand tolerable safety profile in patients with FGFR-aberrant advancedcholangiocarcinoma.

1. A method of treating cholangiocarcinoma in a patient comprising:evaluating a biological sample from the patient for the presence of oneor more FGFR mutants including at least the FGFR2 SNP C383R; andtreating the patient with an FGFR inhibitor if one or more FGFR mutantsincluding at least the FGFR2 SNP C383R are present in the sample.
 2. Amethod of treating cholangiocarcinoma in a patient harboring the FGFR2SNP C383R comprising administering a FGFR inhibitor to said patient. 3.(canceled)
 4. (canceled)
 5. The method according to claim 1 wherein theFGFR inhibitor is erdafitinib.
 6. The method according to claim 5wherein the erdafitinib is administered at a dose of 10 mg.
 7. Themethod according to claim 6 wherein the dose of 10 mg is administeredintermittently.
 8. The method according to claim 7 wherein theerdafitinib is administered at a dose of 10 mg intermittently 7 dayson/7 days off.
 9. The method according to claim 5 wherein theerdafitinib is administered at a dose of 8 mg once daily.